This application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsins B, K, L or S.
Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increased expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B levels and redistribution of the enzyme are found in tumors; thus, suggesting a role for the enzyme in tumor invasion and metastasis. In addition, aberrant cathepsin B activity is implicated in such disease states as rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.
The prominent expression of cathepsin K in osteoclasts and osteoclast-related multinucleated cells and its high collagenolytic activity suggest that the enzyme is involved in osteoclast-mediated bone resorption and, hence, in bone abnormalities such as occurs in osteoporosis. In addition, cathepsin K expression in the lung and its elastinolytic activity suggest that the enzyme plays a role in pulmonary disorders as well.
Cathepsin L is implicated in normal lysosomal proteolysis as well as several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer""s disease and certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis. In addition, cathepsin S is implicated in: allergic disorders, including, but not limited to asthma; and allogenic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts.
In view of the number of diseases wherein it is recognized that an increase in cysteine protease activity contributes to the pathology and/or symptomatology of the disease, molecules which are shown to inhibit the activity of this class of enzymes, in particular molecules which are inhibitors of cathepsins B, K, L and/or S, will be useful as therapeutic agents.
This Application relates to compounds of Formula I: 
in which:
X1 is selected from a group consisting of xe2x80x94CR4R5xe2x80x94, xe2x80x94CR6R7xe2x80x94 and xe2x80x94NR7xe2x80x94, wherein:
R4 and R5 along with the carbon atom to which they are attached represents 
xe2x80x83where
R31 and R32 independently represent hydrogen or hydroxy, alternatively R31 and R32 can be taken together to represent an oxo (xe2x95x90O) group;
R6 is hydrogen or (C1-6)alkyl; and
R7 is (C1-8)alkyl or (CH2)1-3 cyclopropyl;
R1 is hydrogen or (C1-6)alkyl;
R2 is selected from a group consisting of hydrogen and R2a; alternatively R1 and R2 together represent C2-5 alkylene or xe2x80x94CH2NR8CH2xe2x80x94, or both R1 and R2 simultaneously represent fluoro;
R2a represents (C1-8) alkyl optionally substituted with a group selected from xe2x80x94NR8R35, xe2x80x94NR8C(O)R35, xe2x80x94NR8C(O)OR35, xe2x80x94NR8C(O)NR8R35, xe2x80x94NR8C(NR8)NR8R35, xe2x80x94OR35, xe2x80x94SR35, xe2x80x94S(O)R35, xe2x80x94S(O)2R35, xe2x80x94C(O)R35, xe2x80x94C(O)OR35, xe2x80x94OC(O)R35, xe2x80x94C(O)NR8R35, xe2x80x94OC(O)NR8R35, xe2x80x94S(O)2NR8R35, xe2x80x94P(O)(OR8)OR35, xe2x80x94OR52, xe2x80x94CONR8R52, xe2x80x94SO2NR8R52 and xe2x80x94OP(O)(OR8)OR35;
R35 is selected from a group consisting of (C1-4)alkyl, xe2x80x94(CH2)0-3(C3-12)cycloalkyl, xe2x80x94CH2)0-3hetero(C5-10)cycloalkyl, xe2x80x94(CH2)0-3(C6-10)aryl, xe2x80x94CH2)0-3hetero(C5-10)aryl, xe2x80x94(CH2)0-3(C9-10)bicycloaryl and -(CH2)0-3hetero(C8-10)bicycloaryl;
R3 is selected from a group consisting of (C6-10)aryl, (C3-10)cycloalkyl, (C3-10)heterocycloalkyl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl, wherein:
R3 may be substituted further by a radical selected from a group consisting of xe2x80x94X3NR8R21, xe2x80x94X3NR8C(O)R21, xe2x80x94X3NR8C(O)OR21, xe2x80x94X3NR8C(O)NR8R21, xe2x80x94X3NR8C(NR8)NR8R21, xe2x80x94X3OR21, xe2x80x94X3SR21, xe2x80x94X3S(O)R21, xe2x80x94X3S(O)2R21, xe2x80x94X3C(O)R21, xe2x80x94X3C(O)OR21, xe2x80x94X3OC(O)R21, xe2x80x94X3C(O)NR8R21, xe2x80x94X3OC(O)NR8R21, xe2x80x94X3S(O)2NR8R21, xe2x80x94X3P(O)(OR8)OR21, xe2x80x94X3OR52, xe2x80x94X3CONR8R52, xe2x80x94X3SO2NR8R52, xe2x80x94X3OP(O)(OR8)OR21 and xe2x80x94R21, wherein:
X3 is a bond or (C1-6)alkylene, R8 at each occurrence independently is hydrogen or (C1-6)alkyl, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2N(CH3)2 or xe2x80x94CH2CN, and R21 is xe2x80x94(C1-8)alkyl or xe2x80x94X3R22, wherein X3 is as defined above and R22 is selected from a group consisting of (C3-10)cycloalkyl, hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl, wherein:
R22 may be substituted further by a radical selected from a group consisting of xe2x80x94X3NR8R23, xe2x80x94X3NR8C(O)R23, xe2x80x94X3NR8C(O)OR23, xe2x80x94X3NR8C(O)NR8R23, xe2x80x94X3OR23, xe2x80x94X3NR8C(NR8)NR8R23, xe2x80x94X3SR23, xe2x80x94X3S(O)R23, xe2x80x94X3S(O)2R23, xe2x80x94X3C(O)R23, xe2x80x94X3OC(O)R23, xe2x80x94X3C(O)OR23, xe2x80x94X3C(O)NR8R23, xe2x80x94X3OC(O)NR8R23, xe2x80x94X3S(O)2NR8R23, xe2x80x94X3OR52, xe2x80x94X3CONR8R52, xe2x80x94X3SO2NR8R52, xe2x80x94X3P(O)(OR8)OR23, xe2x80x94X3OP(O)(OR8)OR23 and xe2x80x94R23, wherein:
X3 is a bond or (C1-6)alkylene and R8 at each occurrence independently is hydrogen or (C1-6)alkyl, R52 represents CH2CH2xe2x80x94N(CH2CH2OH)2, CH(CH3)CH2N(CH3)2, CH2CH2OH, CH2CH2N(CH3)2 or CH2CN, and R23 is (C1-8)alkyl or xe2x80x94X3R24, wherein X3 is as defined above and R24 is selected from a group consisting of (C3-10)cycloalkyl, hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl, wherein
R24 may be substituted further by a radical selected from a group consisting of xe2x80x94X3NR8R25, xe2x80x94X3NR8C(O)R25, xe2x80x94X3NR8C(O)OR25, xe2x80x94X3OR25, xe2x80x94X3NR8C(O)NR8R25, xe2x80x94X3NR8C(NR8)NR8R25, xe2x80x94X3SR25, xe2x80x94X3S(O)R25, xe2x80x94X3S(O)2R25, xe2x80x94X3C(O)R25, xe2x80x94X3OC(O)R25, xe2x80x94X3C(O)OR25, xe2x80x94X3C(O)NR8R25, xe2x80x94X3OC(O)NR8R25, xe2x80x94X3S(O)2NR8R25, xe2x80x94X3P(O)(OR8)OR25, xe2x80x94X3OR52, xe2x80x94X3CONR8R52, xe2x80x94X3SO2NR8R52, xe2x80x94X3OP(O)(OR8)OR25 and xe2x80x94R25, wherein:
X3 is a bond or (C1-6)alkylene and R8 at each occurrence independently is hydrogen or (C1-6)alkyl, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2N(CH3)2 or xe2x80x94CH2CN, and R25 is xe2x80x94(C1-8)alkyl or xe2x80x94X3R26, wherein X3 is as defined above and R26 is selected from a group consisting of (C3-10)cycloalkyl, hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl; wherein any of the (C3-10)cycloalkyl, hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl contained within R3, R22, R24 and R26 may be substituted further with up to five substituents selected from a group consisting of (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, nitro, halo-substituted (C1-3)alkyl, xe2x80x94X3NR16R16, xe2x80x94X3NR16C(O)OR16, xe2x80x94X3NR16C(O)NR16R16, xe2x80x94X3NR16C(NR16)NR16R16, xe2x80x94X3OR16, xe2x80x94X3SR16, xe2x80x94X3C(O)OR16, xe2x80x94X3C(O)NR16R16, xe2x80x94X3S(O)2NR16R16, xe2x80x94X3P(O)(OR8)OR16, xe2x80x94X3OR52, xe2x80x94X3CONR8R52, xe2x80x94X3C(O)R16, xe2x80x94X3SO2NR8R52, xe2x80x94X3S(O)R17, xe2x80x94X3OP(O)(OR8)OR16, xe2x80x94X3NR16C(O)R17, xe2x80x94X3S(O)2R17 and xe2x80x94X3C(O)R16, wherein:
X3 is a bond or (C1-6)alkylene, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2N(CH3)2 or xe2x80x94CH2CN, R16 at each occurrence independently is selected from a group consisting of hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R17 is xe2x80x94(C1-3)alkyl or halo-substituted (C1-3)alkyl; and
the N-oxide derivatives, prodrug derivatives, protected derivatives, individual stereo isomers and mixtures of stereo isomers, and pharmaceutically acceptable salts thereof, with the proviso that only one of R3, R22, R24 and R26 represents a fused bicyclic ring structure.
A second aspect of this invention is a pharmaceutical composition that contains a compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
A third aspect of this invention is a method of treating a disease in an animal in which inhibition of a cysteine protease can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease. Said method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof.
A fourth aspect of this invention is the processes for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivative, protected derivatives, individual isomers and mixtures of isomers, and the pharmaceutically acceptable salts thereof as set forth in xe2x80x9cDetailed Description of the Inventionxe2x80x9d.
Definitions
Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the meanings given this Section:
xe2x80x9cAlicyclicxe2x80x9d means a moiety characterized by arrangement of the carbon atoms in closed non-aromatic ring structures having properties resembling those of aliphatics and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAliphaticxe2x80x9d means a moiety characterized by straight or branched chain arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.
xe2x80x9cAlkylxe2x80x9d represented by itself means a straight or branched, saturated or unsaturated, aliphatic radical having the number of carbon atoms indicated (e.g., (C1-6)alkyl includes methyl, ethyl, propyl, 2-methylpropyl, butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g., as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond (e.g., (C6-10)aryl(C0-6)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-phenylpropyl, and the like). An alkyl group can be substituted with one or more groups selected from xe2x80x94NH2, xe2x80x94NH(CH3)1-4, xe2x80x94N[(CH3)1-4]2, xe2x80x94OH and xe2x80x94OCH3.
xe2x80x9cAlkylenexe2x80x9d, unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g., (C2-5)alkylene includes ethylene (xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH(CH3)xe2x80x94), 1-methylethylene (xe2x80x94CH(CH3)CH2xe2x80x94), trimethylene (xe2x80x94CH2CH2CH2xe2x80x94), tetramethylene (xe2x80x94CH2CH2CH2CH2xe2x80x94), pentamethylene (xe2x80x94CH2CH2CH2CH2CH2xe2x80x94), and the like). Thus, a compound of Formula I in which R1 together with R2 forms pentamethylene is depicted by the following illustration: 
wherein R1, R2 and R3 are as defined in the Summary of the Invention.
xe2x80x9cAlkylidenexe2x80x9d means a straight or branched saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g., (C1-6)alkylidene includes methylene (CH2), ethylidene (CHCH3), isopropylidene (C(CH3)2), propylidene (CHCH2CH3), allylidene (CHCH CH2), and the like).
xe2x80x9cAminoxe2x80x9d means the radical xe2x80x94NH2. Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
xe2x80x9cAnimalxe2x80x9d includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, non-human primates such as monkeys, apes, etc., or the like) and non-mammals (e.g., birds, or the like).
xe2x80x9cAromaticxe2x80x9d means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2.
xe2x80x9cArylxe2x80x9d means a monocyclic or fused bicyclic aromatic ring assembly containing the total number of ring carbon atoms indicated. For example, optionally substituted (C6-10)aryl as used in this Application includes phenyl, 3-bromophenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, 3-[2-(1-methylpyrrolidin-2-yl)-ethoxycarbonylamino]phenyl, morpholin-4-ylcarbonylmethyl, 3-(2-morpholin-4-ylethoxycarbonylamino)phenyl, 3-[3-(3-morpholin-4-ylpropyl)ureido]phenyl, naphth-1-yl, naphth-2-yl, 3-nitrophenyl, 4-nitrophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, phenyl, 4-(3-pyrid-3-ylmethylureido)phenyl, 4-(3-pyrid-4-ylmethylureido)phenyl, 3-pyrid-3-ylphenyl, 4-(3-pyrid-4-ylureido)phenyl, 4xe2x80x2-sulfamoylbiphenyl-3-yl, 3-thien-3-ylphenyl, and the like.
xe2x80x9cBicycloarylxe2x80x9d means a bicyclic ring assembly containing the number of ring carbon atoms indicated, wherein the rings are fused and one, but not both, of the rings comprising the assembly is aromatic, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C9-10)bicycloaryl includes 1,2-dihydronaphthyl, 5,6,7,8-tetrahydronaphth-1-yl, 2,4-dioxo-1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, and the like).
xe2x80x9cCarbamoylxe2x80x9d means the radical xe2x80x94C(O)NH2. Unless indicated otherwise, the compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and protected derivatives fall within the scope of the invention.
xe2x80x9cCarbocyclic ketone, thioketone or iminoketone derivativexe2x80x9d means an alicyclic derivative wherein one or more ring members are substituted by an oxo (xe2x95x90O), thioxo (xe2x95x90S) or imino (xe2x95x90NR) group, wherein R is hydrogen, (C1-6)alkyl or a protecting group (e.g., 1-oxoindan-5-yl, 3-thioxocyclohexyl, 5-iminopiperidin-3-yl, and the like).
xe2x80x9cCarboxyxe2x80x9d means the radical xe2x80x94C(O)OH. Unless indicated otherwise, the compounds of the invention containing carboxy moieties include protected derivatives thereof. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a saturated or partially unsaturated, monocyclic ring, or bridged polycyclic ring assembly containing the number of ring carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C3-10)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like).
xe2x80x9cDiseasexe2x80x9d specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the xe2x80x9cside effectsxe2x80x9d of such therapy.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo. xe2x80x9cHeteroarylxe2x80x9d means aryl, as defined in this Application, provided that one or more of the ring carbon atoms indicated are replaced by a hetero atom moiety selected from N, NR, O or S, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and each ring is comprised of 5 or 6 ring atoms. For example, optionally substituted hetero(C5-10)aryl as used in this Application includes 4-(3-aminophenyl)thiazol-2-yl, 3-(6-aminopyrid-3-yl)phenyl, 2-dimethylaminothiazol-4-yl, 3-(4,6-dimethylpyrid-2-yl)phenyl, 6-methoxypyrid-3-yl, 2-(4-morpholin-4-ylphenyl)thiazol-4-yl, 4-(3-nitrophenyl)thiazol-2-yl, 2-phenylthiazol-4-yl, 4-phenylthiazol-2-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 2-pyrid-4-ylaminothiazol-4-yl, 3-pyrid-2-ylphenyl, 3-pyrid-3-ylphenyl, 3-pyrid-4-ylphenyl, 2-pyrid-4-ylthiazol-4-yl, 4-pyrid-4-ylthiazol-2-yl, 4-(4-pyrrolidin-1-ylphenyl)thiazol-2-yl, thien-2-yl, thien-3-yl, thien-2-ylphenyl, thiazol-2-ylphenyl, 6-bromopyrid-2-ylphenyl, 6-bromopyrid-3-ylphenyl, 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)phenyl, 3-(2,3-dihydrobenzo[1,3]dioxol-5-yl)phenyl, indol-1-yl, and the like. Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
xe2x80x9cHeterobicycloarylxe2x80x9d means bicycloaryl, as defined in this Application, provided that one or more of the ring carbon atoms indicated are replaced by a hetero atom moiety selected from N, NR, O, S or B, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. In general, the term heterobicycloaryl as used in this Application includes, for example, benzo[1,3]dioxol-5-yl, 3,4-dihydro-2H-[1,8]naphthyridinyl, 3,4-dihydro-2H-quinolinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl, 3-oxo-2,3-dihydrobenzo[1,4]oxazinyl, 5,6,7,8-tetrahydroquinolinyl, and the like. Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
xe2x80x9cHeterocycloalkylxe2x80x9d means cycloalkyl, as defined in this Application, provided that one or more of the ring carbon atoms indicated are replaced by a hetero atom moiety selected from N, NR, O, S or B, wherein R is hydrogen, (C1-6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term heterocyclo(C5-10)alkyl includes imidazolidinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like). For example, optionally substituted hetero(C5-10)cycloalkyl as used in this Application to define R3 includes morpholin-4-yl, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl, tetrahydrofur-2-yl, and the like. Suitable protecting groups include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
xe2x80x9cHydroxyxe2x80x9d means the radical OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like.
xe2x80x9cIsomersxe2x80x9d mean compounds of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and stereoisomers that are nonsuperimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d or sometimes xe2x80x9coptical isomersxe2x80x9d. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral centerxe2x80x9d. A compound with one chiral center has two enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixturexe2x80x9d. A compound that has more than one chiral center has 2nxe2x88x921 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixturexe2x80x9d. When one chiral center is present a stereoisomer may be characterized by the absolute configuration of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. Enantiomers are characterized by the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 3rd edition, March, Jerry, John Wiley and Sons, New York, 1985). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all possible stereoisomers.
xe2x80x9cLeaving groupxe2x80x9d has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes, halogen, hydroxy, alkyloxy, alkylsulfonloxy (e.g., mesyloxy, ethanesulfonyloxy, or the like), arylsulfonyloxy (e.g., benzenesulfonyloxy and tosyloxy, thienyloxy), dihalophosphinoyloxy, tetrahalophosphaoxy, and the like.
xe2x80x9cNitroxe2x80x9d means the radical NO2.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase xe2x80x9cR3 can be optionally substitutedxe2x80x9d means that the moiety referred to may or may not contain substituents in order to fall within the scope of the invention.
xe2x80x9cN-oxide derivativesxe2x80x9d means derivatives of compounds of Formula I in which nitrogens are in an oxidized state (i.e., Oxe2x80x94N) and which possess the desired pharmacological activity.
xe2x80x9cOxoxe2x80x9d means the radical xe2x95x90O.
xe2x80x9cPathologyxe2x80x9d of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d means salts of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, ammonium hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine and the like.
xe2x80x9cProdrug derivativesxe2x80x9d means derivatives of compounds of Formula I which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I.
xe2x80x9cProtected derivativesxe2x80x9d means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protective groups. Protected derivatives of compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cysteine protease inhibitors. A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981.
xe2x80x9cTherapeutically effective amountxe2x80x9d means that amount which, when administered to an animal for treating a disease, is, by itself or in combination with additional active ingredients, sufficient to effect such treatment for the disease.
xe2x80x9cTreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any administration of a compound of the present invention and includes:
(1) Preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
(2) Inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or
(3) Ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
xe2x80x9cUreidoxe2x80x9d means the radical xe2x80x94NHC(O)NH2. Unless indicated otherwise, the compounds of the invention containing ureido moieties include protected derivatives thereof. Suitable protective groups for ureido moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. For example, a compound of Formula I wherein the R1 contains an ureido radical may exist as either the unprotected or a protected derivative and both the unprotected and protected derivatives fall within the scope of the invention.
Specific Embodiments of the Invention
While the broadest definition of this invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred. One preferred embodiment provides compounds of Formula I in which:
X1 is xe2x80x94CR4R5xe2x80x94 or xe2x80x94CHR7xe2x80x94;
R6 is H;
R7 is (C4-8) branched alkyl or xe2x80x94CH2-cyclopropyl;
R1 is hydrogen;
R2 is hydrogen or R2a; alternatively, R1 and R2 together represent xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94NR8xe2x80x94CH2xe2x80x94;
R2a represents (C2-4) alkyl optionally substituted with a group selected from xe2x80x94NR8C(O)OR35, xe2x80x94OR35, xe2x80x94SR35, xe2x80x94S(O)R35, xe2x80x94S(O)2R35, xe2x80x94C(O)R35, xe2x80x94SO2NR8R52 and xe2x80x94OP(O)(OR8)OR35;
R3 is (C6-10)aryl or hetero(C5-10)aryl, wherein R3 may be substituted further by a radical selected from a group consisting of xe2x80x94X3NR8R21, xe2x80x94X3NR8C(O)R21, xe2x80x94X3NR8C(O)OR21, xe2x80x94X3NR8C(O)NR8R21, xe2x80x94X3OR21, xe2x80x94X3SR21, xe2x80x94X3C(O)R21, xe2x80x94X3C(O)OR21, xe2x80x94X3OC(O)R21, xe2x80x94X3C(O)NR8R21, xe2x80x94X3OR52, xe2x80x94X3CONR8R52 and xe2x80x94R21, wherein:
X3 is a bond or (C1-6)alkylene, R8 at each occurrence independently is hydrogen or (C1-6)alkyl and R21 is (C1-8)alkyl or xe2x80x94X3R22, wherein X3 is as defined above;
R22 is selected from a group consisting of hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl and hetero(C8-10)bicycloaryl, wherein R22 may be substituted further by a radical selected from a group consisting of (C1-4)alkyl, xe2x80x94X3NR8R23, xe2x80x94X3C(O)NR8R52, xe2x80x94X3OR23, xe2x80x94X3NR8C(O)OR23, xe2x80x94X3SO2NR8R52, xe2x80x94X3C(O)NR8R23, xe2x80x94X3SO2NR8R23, xe2x80x94X3COR23, xe2x80x94X3OR52, xe2x80x94X3S(O)2R23, X3N(R8)2 and xe2x80x94R23, wherein X3 is a bond or (C1-6)alkylene, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CN or xe2x80x94CH2CH2N(CH3)2, R8 at each occurrence independently is hydrogen or (C1-6)alkyl and R23 is (C1-8)alkyl or xe2x80x94X3R24, wherein X3 is as defined above;
R24 is selected from a group consisting of hetero(C5-10)cycloalkyl and hetero(C5-10)aryl, wherein R24 may be substituted further with R25, xe2x80x94X3OR52, xe2x80x94X3NR8R25, xe2x80x94X3COOR25 and xe2x80x94X3SO2NR8R52; wherein X3 is a bond or (C1-6)alkylene, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CN or xe2x80x94CH2CH2N(CH3)2, R8 at each occurrence independently is hydrogen or (C1-6)alkyl and R25 is (C1-8)alkyl or xe2x80x94X3R26, wherein X3 is as defined above;
R26 is hetero(C5-10)cycloalkyl; and wherein any of the (C3-10)cycloalkyl, hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl contained within R3, R22, R24 and R26 may be substituted further with up to five substituents selected from a group consisting of (C1-6)alkyl, cyano, halo, nitro, halo-substituted (C1-3alkyl, xe2x80x94X3NR16R16, xe2x80x94X3OR52 and xe2x80x94X3C(O)R16, wherein:
X3 is a bond or (C1-6)alkylene, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2N(CH3)2 or xe2x80x94CH2CN, R16 at each occurrence independently is selected from a group consisting of hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R17 is xe2x80x94(C1-3)alkyl or halo-substituted (C1-3)alkyl; and
the N-oxide derivatives, prodrug derivatives, protected derivatives, individual stereo isomers and mixtures of stereo isomers, and pharmaceutically acceptable salts thereof, with the proviso that only one of R3, R22, R24 and R26 represents a fused bicyclic ring structure.
A further preferred embodiment of the present invention provides compounds of Formula I wherein:
X1 is xe2x80x94CHR7xe2x80x94;
R7 is i-propyl;
R2 is hydrogen or R2a;
R2a represents (C4) alkyl optionally substituted with a group selected from xe2x80x94NR8C(O)OR35 or xe2x80x94SR35;
R3 is phenyl or hetero(C5-6)aryl, wherein R3 may be substituted further by a radical selected from a group consisting of xe2x80x94X3NR8R21, xe2x80x94X3NR8C(O)R21, xe2x80x94X3NR8C(O)OR21 and xe2x80x94R21;
R21 is xe2x80x94X3R22;
R22 is selected from a group consisting of hetero(C5-6)cycloalkyl, (C6)aryl, hetero(C5-10)aryl and hetero(C8-9)bicycloaryl, wherein R22 can be optionally substituted further by a radical selected from a group consisting of (C1-4)alkyl, xe2x80x94X3OR23, xe2x80x94X3NR8R23, xe2x80x94X3C(O)NR8R23, xe2x80x94X3C(O)NR8R52, xe2x80x94X3SO2NR8R23 and R23; wherein X3 is a bond or (C1-6)alkylene, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CN or xe2x80x94CH2CH2N(CH3)2, R8 at each occurrence independently is hydrogen or (C1-6)alkyl and R23 is (C1-8)alkyl or xe2x80x94X3R24, wherein X3 is as defined above;
R24 is selected from a group consisting of hetero(C5-6)cycloalkyl and hetero(C5-6)aryl, wherein R24 may be substituted further with R25, xe2x80x94X3OR52, xe2x80x94X3NR8R25, xe2x80x94X3COOR25 and xe2x80x94X3SO2NR8R52; wherein X3 is a bond or (C1-6)alkylene, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CN or xe2x80x94CH2CH2N(CH3)2, R8 at each occurrence independently is hydrogen or (C1-6)alkyl and R25 is (C1-4)alkyl or xe2x80x94X3R26, wherein X3 is as defined above;
R26 is hetero(C5-10)cycloalkyl; and wherein the (C3-10)cycloalkyl contained within R26 may be substituted further with up to three groups selected from a group consisting of (C1-2)alkyl.
Another preferred embodiment provides compounds of Formula I wherein:
R2 is hydrogen;
R3 is phenyl or hetero(C5-6)aryl, wherein R3 is substituted by xe2x80x94R21;
R21 is xe2x80x94X3R22;
X3 is a bond;
R22 is hetero(C6)aryl and hetero(C5-6)aryl; wherein R22 is substituted further by R23;
R23 is xe2x80x94X3R24, wherein X3 is a bond;
R24 is hetero(C5-6)aryl, wherein R24 may be substituted further with R25, xe2x80x94X3OR52, xe2x80x94X3NR8R25, xe2x80x94X3COOR25 or xe2x80x94X3SO2NR8R52; wherein X3 is a bond or (C1-6)alkylene, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CN or xe2x80x94CH2CH2N(CH3)2, R8 at each occurrence independently is hydrogen or (C1-6)alkyl and R25 is xe2x80x94X3R26, wherein X3 is a bond; and
R26 is hetero(C5-6)cycloalkyl substituted with up to two (0-2) groups selected from a group consisting of (C1-2)alkyl.
In yet another preferred embodiment of the present invention are provided compounds of Formula I wherein:
R1 and R2 is hydrogen;
R3 is phenyl or hetero(C5-6)aryl, wherein R3 is substituted by xe2x80x94R21;
R21 is xe2x80x94X3R22;
xe2x80x94X3 is a bond;
R22 is hetero(C5-6)aryl; wherein R22 is substituted by xe2x80x94R23;
R23 is xe2x80x94X3R24, wherein X3 is a bond;
R24 is hetero(C5-6)aryl substituted by R25;
R25 is xe2x80x94X3R26, wherein X3 is a bond; and
R26 is hetero(C5-6)cycloalkyl substituted with up to two (0-2) groups selected from a group consisting of (C1-2)alkyl.
Particularly preferred compounds of Formula I of the present invention are:
4-Methyl-2-[3xe2x80x2-(2-piperazin-1-yl-thiazol-4-yl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{3xe2x80x2-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-pentanoic acid cyanomethyl-amide;
2-{3xe2x80x2-[2-(4-tert-Butyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
2-{3xe2x80x2-[2-(3-Dimethylamino-pyrrolidin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(2-piperazin-1-yl-thiazol-4-yl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{4xe2x80x2-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{3xe2x80x2-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-pentanoic acid (1-cyano-cyclopropyl)-amide;
4-Methyl-2-[3xe2x80x2-(2-piperazin-1-ylmethyl-thiazol-4-yl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{4xe2x80x2-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-pentanoic acid (1-cyano-cyclopropyl)-amide;
4-Methyl-2-{3xe2x80x2-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{3xe2x80x2-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-pentanoic acid cyanomethyl-amide;
2-{3xe2x80x2-[2-(4-tert-Butyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(2-piperazin-1-yl-thiazol-4-yl)-biphenyl-3-yl]-pentanoic acid (1-cyano-cyclopropyl)-amide;
4-Methyl-2-{4xe2x80x2-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-pentanoic acid (1-cyano-cyclopropyl)-amide;
4-Methyl-2-(4xe2x80x2-piperazin-1-yl-biphenyl-3-yl)-pentanoic acid (1-cyano-cyclopropyl)-amide;
4-Methyl-2-[3xe2x80x2-(pyrrolidin-2-ylmethoxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-[4xe2x80x2-(4-tert-Butyl-piperazin-1-yl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-(4xe2x80x2-piperazin-1-yl-biphenyl-3-yl)-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(1,2,3,6-tetrahydro-pyridin-4-yl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(4-methyl-piperazin-1-yl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-[4xe2x80x2-(4-tert-Butyl-piperazin-1-yl)-biphenyl-3-yl]-4-methyl-pentanoic acid (1-cyano-cyclopropyl)-amide;
4-Methyl-2-{4xe2x80x2-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-biphenyl-3-yl}-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3xe2x80x2-(pyrrolidin-2-ylmethoxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(pyrrolidin-2-ylmethoxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(pyrrolidin-2-ylmethoxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3xe2x80x2-(1-methyl-pyrrolidin-3-ylmethyl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-{4xe2x80x2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-biphenyl-3-yl}-4-methyl-pentanoic acid (1-cyano-cyclopropyl)-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-carboxylic acid methyl-(1-methyl-pyrrolidin-3-yl)-amide;
4-Methyl-2-[3xe2x80x2-(pyrrolidin-3-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-(4xe2x80x2-piperazin-1-yl-biphenyl-3-yl)-pentanoic acid cyanomethyl-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide;
4-Methyl-2-[3xe2x80x2-(pyrrolidin-3-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3-(7-nitro-1H-indol-4-yl)-phenyl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3xe2x80x2-(pyrrolidin-3-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;
2-{3xe2x80x2-[1-(2-Hydroxy-ethyl)-piperidin-4-ylmethyl]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
2-(3-{5-[4-(2-Hydroxy-ethyl)-piperazine-1-sulfonyl]-thiophen-2-yl}-phenyl)-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{3-[2-(4-methyl-piperazin-1-yl)-thiazol-5-yl]-phenyl}-pentanoic acid cyanomethyl-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide;
4-Methyl-2-[4xe2x80x2-(piperidin-4-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{3-[5-(4-methyl-piperazine-1-sulfonyl)-thiophen-2-yl]-phenyl}-pentanoic acid cyanomethyl-amide;
2-{3-[3-(2-Amino-ethyl)-1H-indol-5-yl]-phenyl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(pyrrolidin-3-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-[3xe2x80x2-(2-Dimethylamino-thiazol-4-yl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
N-(cyanomethyl)-4-methyl-2-[3-(pyrid-2-yl)phenyl]pentanamide;
N-(cyanomethyl)-2-[3-(1H-indol-5-yl)phenyl]-4-methylpentanamide;
N-(cyanomethyl)-2-[3-(1H-indol-6-yl)phenyl]-4-methylpentanamide;
N-cyanomethyl-2-(4xe2x80x2-methylsulfonylbiphenyl-3-yl)-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(5-pyrimidinyl)phenyl]pentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(2-pyrimidinyl)phenyl]pentanamide;
3xe2x80x2-(1-cyanomethylcarbamoyl)-3-methylbutyl]biphenyl-4-carboxamide;
N-(cyanomethyl)-2-[3-(4-isoquinolinyl)phenyl]-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(3-quinolinyl)phenyl]pentanamide;
2-[4xe2x80x2-(acetylamino)[1,1xe2x80x2-biphenyl]-3-yl]-N-(cyanomethyl)-4-methylpentanamide;
N-(cyanomethyl)-2-[3-(3-furyl)phenyl]-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(2-methyl-6-quinolinyl)phenyl]pentanamide;
N-(cyanomethyl)-2-[3-(4,5-dichloro-1H-imidazol-2-yl)phenyl]-4-methylpentanamide;
N-(cyanomethyl)-2-[3-(3,5-dimethyl-4-isoxazolyl)phenyl]-4-methylpentanamide;
tert-butyl 3xe2x80x2-(1-cyanomethylcarbamoyl-3-methylbutyl)biphenyl-4-ylcarbamate;
N-(cyanomethyl)-4-methyl-2-[3-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl]pentanamide;
N-(cyanomethyl)-2-(3-methoxyphenyl)-4-methylpentanamide;
2,2-dichloroethyl 3xe2x80x2-(1-cyanomethylcarbamoyl-3-methylbutyl)biphenyl-4-ylcarbamate;
N-(cyanomethyl)-4-methyl-2-(4xe2x80x2-phenoxy[1,1xe2x80x2-biphenyl]-3-yl)pentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)phenyl]pentanamide;
3-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)phenyl 2-(3-hydroxyphenyl)-4-methylpentanoate;
tert-butyl 3xe2x80x2-(1-cyanomethylcarbamoyl-3-methylbutyl)biphenyl-4-ylmethylcarbamate;
N-(cyanomethyl)-2-[3-(2,3-dihydro-1H-indol-5-yl)phenyl]-4-methylpentanamide;
tert-butyl N-5-[3-(1-cyanomethylcarbamoyl-3-methylbutyl)phenyl]pyrimidin-2-yl-N-(tert-butoxycarbonyl)carbamate;
N-(cyanomethyl)-4-methyl-2-[3-(1-methyl-1H-indol-5-yl)phenyl]pentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(7-nitro-1H-indol-5-yl)phenyl]pentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]pentanamide;
2-[3-(7-amino-1H-indol-5-yl)phenyl]-N-(cyanomethyl)-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(7-nitro-2,3-dihydro-1H-indol-5-yl)phenyl]pentanamide;
5-[3-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)phenyl]-1H-indole-2-carboxylic acid;
5-[3-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)phenyl]-1H-indole-2-carboxamide;
N-(cyanomethyl)-4-methyl-2-[3-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]pentanamide;
N-(cyanomethyl)-4-methyl-2-[3xe2x80x2-(4-morpholinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
N-(cyanomethyl)-4-methyl-2-[4xe2x80x2-(4-morpholinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
N-(cyanomethyl)-4-methyl-2-[2xe2x80x2-(4-morpholinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
N-(cyanomethyl)-2-(3-{3-[(dimethylamino)methyl]-1H-indol-5-yl}phenyl)-4-methylpentanamide;
2-[4xe2x80x2-(aminomethyl)[1,1xe2x80x2-biphenyl]-3-yl]-N-(cyanomethyl)-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[4xe2x80x2-(4-methyl-1-piperazinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
N-(cyanomethyl)-4-methyl-2-[4xe2x80x2-(1-piperazinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
ethyl 4-[3xe2x80x2-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)[1,1xe2x80x2-biphenyl]-4-yl]-1-piperazinecarboxylate;
2-{3-[3-(2-aminoethyl)-1H-indol-5-yl]phenyl}-N-(cyanomethyl)-4-methylpentanamide;
4-Methyl-2-[3xe2x80x2-(2-piperazin-1-yl-thiazol-4-yl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-(4xe2x80x2-Hydroxy-3xe2x80x2-isoxazol-5-yl-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
2-[4xe2x80x2-(2-Dimethylamino-thiazol-4-yl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
2-[3xe2x80x2-(2-Guanidino-thiazol-4-yl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{3-[5-(4-methyl-piperazine-1-sulfonyl)-thiophen-2-yl]-phenyl}-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{3-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-phenyl}-pentanoic acid cyanomethyl-amide;
N-{3-[5-(3,5-Dichloro-2-hydroxy-phenyl)-1H-pyrazol-3-yl]-propyl}-guanidine;
2-{3-[2-(3,5-Dimethyl-piperazin-1-yl)-thiazol-4-yl]-phenyl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{3-[2-(4-methyl-piperazin-1-yl)-thiazol-5-yl]-phenyl}-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[2-(4-piperazin-1-yl-phenyl)-thiazol-4-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{3xe2x80x2-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-pentanoic acid cyanomethyl-amide;
4-Methyl-2-{4xe2x80x2-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3xe2x80x2-(pyrrolidin-3-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-{3xe2x80x2-[1-(2-Hydroxy-ethyl)-piperidin-4-yloxy]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3xe2x80x2-(piperidin-4-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(piperidin-4-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-{4xe2x80x2-[1-(2-Hydroxy-ethyl)-piperidin-4-yloxy]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(pyrrolidin-3-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-[3xe2x80x2-(2-Dimethylamino-ethoxy)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
4-{3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-yloxy}-piperidine-1-carboxylic acid tert-butyl ester;
4-{3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester;
3-{3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-3-yloxy}-pyrrolidine-1-carboxylic acid tert-butyl ester;
3-{3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-yloxy}-pyrrolidine-1-carboxylic acid tert-butyl ester;
2-[5xe2x80x2-Fluoro-2xe2x80x2-(pyrrolidin-3-yloxy)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
3-{3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-3-yloxy}-pyrrolidine-1-carboxylic acid tert-butyl ester;
4-Methyl-2-[3xe2x80x2-(pyrrolidin-3-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3-(2-piperazin-1-ylmethyl-thiazol-4-yl)-phenyl]-pentanoic acid cyanomethyl-amide;
4-(4-{3-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-phenyl}-thiazol-2-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester;
3-{3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-5-fluoro-biphenyl-2-yloxy}-pyrrolidine-1-carboxylic acid tert-butyl ester;
4-Methyl-2-[3xe2x80x2-(pyrrolidin-3-yloxy)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-(3-Isoquinolin-4-yl-phenyl)-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(toluene-3-sulfonylamino)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-(4xe2x80x2-nitro-biphenyl-3-yl)-pentanoic acid cyanomethyl-amide;
2-(2xe2x80x2,4xe2x80x2-Dimethoxy-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
2-(4xe2x80x2-Methoxy-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
2-(4xe2x80x2-Amino-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
2-(3xe2x80x2-Amino-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-(3xe2x80x2-nitro-biphenyl-3-yl)-pentanoic acid cyanomethyl-amide;
4-Methyl-2-(4xe2x80x2-sulfamoyl-biphenyl-3-yl)-pentanoic acid cyanomethyl-amide;
2-(5xe2x80x2-Acetyl-2xe2x80x2-morpholin-4-yl-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
N-(cyanomethyl)-4-methyl-2-[3-(2-methyl-6-quinolinyl)phenyl]pentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(3-quinolinyl)phenyl]pentanamide;
N-(cyanomethyl)-2-[3-(1H-indol-5-yl)phenyl]-4-methylpentanamide;
4-[(tert-butoxycarbonyl)amino]-3xe2x80x2-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)-1,1xe2x80x2-biphenyl;
4-{[(tert-butoxycarbonyl)amino]methyl}-3xe2x80x2-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)-1,1xe2x80x2-biphenyl;
2-[4xe2x80x2-(aminomethyl)[1,1xe2x80x2-biphenyl]-3-yl]-N-(cyanomethyl)-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(1-methyl-1H-indol-5-yl)phenyl]pentanamide;
2-[3-(7-nitro-1H-indol-5-yl)phenyl]-N-(cyanomethyl)-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(7-nitro-2,3-dihydro-1H-indol-5-yl)phenyl]pentanamide;
2-[3-(7-amino-1H-indol-5-yl)phenyl]-N-(cyanomethyl)-4-methylpentanamide;
N-(cyanomethyl)-2-(3-{3-[(dimethylamino)methyl]-1H-indol-5-yl}phenyl)-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl]pentanamide;
2-{3-[3-(2-aminoethyl)-1H-indol-5-yl]phenyl}-N-(cyanomethyl)-4-methylpentanamide;
(2R)-N-(cyanomethyl)-4-methyl-2-[4xe2x80x2-(4-methyl-1-piperazinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
(2R)-N-(cyanomethyl)-4-methyl-2-[4xe2x80x2-(1-piperazinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
N-(cyanomethyl)-4-methyl-2-[3-(6-quinolinyl)phenyl]pentanamide;
N-(cyanomethyl)-3-cyclopropyl-2-[4xe2x80x2-(4-methyl-1-piperazinyl)[1,1xe2x80x2-biphenyl]-3-yl]propanamide;
N-(cyanomethyl)-4-methyl-2-[4xe2x80x2-(1,2,3,6-tetrahydro-4-pyridinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
(4S)-N-(cyanomethyl)-4-methyl-2-[4xe2x80x2-(4-methyl-1-piperazinyl)[1,1xe2x80x2-biphenyl]-3-yl]hexanamide;
(2R)-N-(cyanomethyl)-2-{4xe2x80x2-[4-(2-hydroxyethyl)-1-piperazinyl][1,1xe2x80x2-biphenyl]-3-yl}-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[2xe2x80x2-(1-piperazinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
(2R)-N-(cyanomethyl)-4-methyl-2-{3-[6-(1-piperazinyl)-3-pyridinyl]phenyl}pentanamide;
(2R)-N-(cyanomethyl)-4-methyl-2-[4xe2x80x2-(4-pyridinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
(2R)-N-(cyanomethyl)-2-{4xe2x80x2-[4-(2-hydroxy-2-methylpropyl)-1-piperazinyl][1,1xe2x80x2-biphenyl]-3-yl}-4-methylpentanamide;
N-(cyanomethyl)-4-methyl-2-[4xe2x80x2-(4-piperidinyl)[1,1xe2x80x2-biphenyl]-3-yl]pentanamide;
4-Methyl-2-[4xe2x80x2-(4-methyl-piperazin-1-yl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-{4xe2x80x2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-biphenyl-3-yl}-4-methyl-pentanoic acid (1-cyano-cyclopropyl)-amide;
4-Methyl-2-[3xe2x80x2-(4-methyl-piperazin-1-yl)-biphenyl-3-yl]-pentanoic acid cyanomethylamide;
2-(3-{2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-yl}-phenyl)-4-methyl-pentanoic acid (1-cyano-cyclopropyl)-amide;
2-Biphenyl-3-yl-4-methyl-pentanoic acid (cyano-methyl-methyl)-amide;
2-Biphenyl-3-yl-4-methyl-pentanoic acid (1-cyano-3-methylsulfanyl-propyl)-amide;
[5-(2-Biphenyl-3-yl-4-methyl-pentanoylamino)-5-cyano-pentyl]-carbamic acid benzyl ester;
4-Methyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-pentanoic acid cyanomethyl-amide;
2-Biphenyl-3-yl-4-methyl-pentanoic acid (1-cyano-pentyl)-amide;
4-Methyl-2-(3xe2x80x2-piperazin-1-yl-biphenyl-3-yl)-pentanoic acid cyanomethyl-amide;
4-{3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-3-yl}-piperazine-1-carboxylic acid tert-butyl ester;
2-(5-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-phenyl}-pyridin-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
2-{5-[4-(4-Formyl-piperazin-1-yl)-phenyl]-pyridin-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[5-(4-piperazin-1-yl-phenyl)-pyridin-3-yl]-pentanoic acid cyanomethyl-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-2-carboxylic acid methyl ester;
2-[3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-phenyl]-4-methyl-pentanoic acid cyanomethyl-amide;
2-[4xe2x80x2-(1-Hydroxy-ethyl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
2-(3xe2x80x2,5xe2x80x2-Bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
2-(4xe2x80x2-Cyano-2xe2x80x2-methyl-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
N-[1-(Cyanomethyl-carbamoyl)-2-(2-fluoro-3-methyl-phenylmethanesulfonyl)-ethyl]-benzamide;
N-[1-(Cyanomethyl-carbamoyl)-2-(2,5-difluoro-phenylmethanesulfonyl)-ethyl]-benzamide;
2-{3xe2x80x2-[4-(2-Hydroxy-ethyl)-piperazine-1-sulfonyl]-4xe2x80x2-methoxy-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-3-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;
4-Methyl-2-[3xe2x80x2-(2-morpholin-4-yl-ethylsulfamoyl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide;
3xe2x80x2-[1-(Cyanomethyl-carbamoyl)-3-methyl-butyl]-biphenyl-4-carboxylic acid methyl-(2-morpholin-4-yl-ethyl)-amide;
2-(3xe2x80x2-Fluoro-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
2-[3-(6-Bromo-pyridin-2-yl)-phenyl]-4-methyl-pentanoic acid cyanomethyl-amide;
2-(2xe2x80x2-Cyano-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
2-(3xe2x80x2-Cyano-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
2(4xe2x80x2-Cyano-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-(3-quinolin-8-yl-phenyl)-pentanoic acid cyanomethyl-amide;
4-Methyl-2-(3-quinolin-3-yl-phenyl)-pentanoic acid cyanomethyl-amide;
4-Methyl-2-(4xe2x80x2-trifluoromethoxy-biphenyl-3-yl)-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3-(5-nitro-thiazol-2-yl)-phenyl]-pentanoic acid cyanomethyl-amide;
2-(4xe2x80x2-Acetylamino-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(4-methyl-piperazine-1-sulfonyl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3xe2x80x2-(4-methyl-piperazine-1-sulfonyl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(piperazine-1-sulfonyl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-{4xe2x80x2-[4-(2-Hydroxy-ethyl)-piperazine-1-carbonyl]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
2-{3xe2x80x2-[4-(2-Hydroxy-ethyl)-piperazine-1-carbonyl]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(2-morpholin-4-yl-ethylsulfamoyl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-(4xe2x80x2-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethylsulfamoyl}-biphenyl-3-yl)-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(3-morpholin-4-yl-propylsulfamoyl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(3-morpholin-4-yl-propylsulfamoyl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
2-[4xe2x80x2-(2-Dimethylamino-1-methyl-ethylsulfamoyl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
2-[4xe2x80x2-(2-Hydroxy-ethylsulfamoyl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
2-[4xe2x80x2-(2-Hydroxy-ethylsulfamoyl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
2-[4xe2x80x2-(3-Dimethylamino-pyrrolidine-1-sulfonyl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide;
2-{3xe2x80x2-[2-(3-Dimethylamino-pyrrolidin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(2-piperazin-1-yl-thiazol-4-yl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
[5-(5-Amino-1H-pyrrolo[3,2-b]pyridin-2-yl)-6,3xe2x80x2-dihydroxy-biphenyl-3-yl]-acetic acid;
2-{3xe2x80x2-[2-(4-tert-Butyl-piperazin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
2-{3xe2x80x2-[2-(3-Dimethylamino-pyrrolidin-1-yl)-thiazol-4-yl]-biphenyl-3-yl}-4-methyl-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[3xe2x80x2-(2-piperazin-1-yl-thiazol-4-yl)-biphenyl-3-yl]-pentanoic acid (1-cyano-cyclopropyl)-amide;
4-Methyl-2-[3xe2x80x2-(2-piperazin-1-ylmethyl-thiazol-4-yl)-biphenyl-3-yl]-pentanoic acid cyanomethyl-amide;
4-Methyl-2-[4xe2x80x2-(2-piperazin-1-yl-thiazol-4-yl)-biphenyl-3-yl]-pentanoic acid (1-cyano-cyclopropyl)-amide;
4-Methyl-2-{4xe2x80x2-[methyl-(1-methyl-pyrrolidin-3-yl)-sulfamoyl]-biphenyl-3-yl}-pentanoic acid cyanomethyl-amide; and
2-[4xe2x80x2-(4-Formyl-piperazine-1-sulfonyl)-biphenyl-3-yl]-4-methyl-pentanoic acid cyanomethyl-amide; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts thereof.
Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable excipient(s). A preferred pharmaceutical composition further comprises one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effective amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof.
A preferred bisphosphonic acid is selected from the group consisting of 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof.
A particularly preferred pharmaceutical composition is one wherein the bisphosphonic acid is 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof. The preferred pharmaceutical salt of the bisphonic acid is 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.
In yet another aspect of the present invention is provided a method for treating a disease in an animal in which inhibition of a cysteine protease can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of claim 1 or a N-oxide derivative or individual isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt thereof; preferably the disease treated is osteoporosis.
The present invention in yet another aspect provides a process for preparing a compound of Formula I: 
X1 is selected from a group consisting of xe2x80x94CR4R5xe2x80x94, xe2x80x94CR6R7xe2x80x94 and xe2x80x94NR7xe2x80x94, wherein:
R4 and R5 along with the carbon atom to which they are attached represents 
xe2x80x83where R31 and R32 independently represent hydrogen or hydroxy, alternatively R31 and R32 can be taken together to represent an oxo (xe2x95x90O) group;
R6 is hydrogen or (C1-6)alkyl; and
R7 is (C1-8)alkyl or (CH2)1-3 cyclopropyl;
R1 is hydrogen or (C1-6)alkyl;
R2 is selected from a group consisting of hydrogen and R2a;
alternatively R1 and R2 together represent C2-5 alkylene or xe2x80x94CH2NR8CH2xe2x80x94, or both R1 and R2 simultaneously represent fluoro;
R2a represents (C1-8) alkyl optionally substituted with a group selected from xe2x80x94NR8R35, xe2x80x94NR8C(O)R35, xe2x80x94NR8C(O)OR35, xe2x80x94NR8C(O)NR8R35, xe2x80x94NR8C(NR8)NR8R35, xe2x80x94OR35, xe2x80x94SR35, xe2x80x94S(O)R35, xe2x80x94S(O)2R35, xe2x80x94C(O)R35, xe2x80x94C(O)OR35, xe2x80x94OC(O)R35, xe2x80x94C(O)NR8R35, xe2x80x94OC(O)NR8R35, xe2x80x94S(O)2NR8R35, xe2x80x94P(O)(OR8)OR35, xe2x80x94OR52, xe2x80x94CONR8R52, xe2x80x94SO2NR8R52 and xe2x80x94OP(O)(OR8)OR35;
R35 is selected from a group consisting of (C1-4)alkyl, xe2x80x94(CH2)0-3(C3-12)cycloalkyl, xe2x80x94(CH2)0-3hetero(C5-10)cycloalkyl, xe2x80x94(CH2)0-3(C6-10)aryl, xe2x80x94(CH2)0-3hetero(C5-10)aryl, xe2x80x94(CH2)0-3(C9-10)bicycloaryl and xe2x80x94(CH2)0-3hetero(C8-10)bicycloaryl;
R3 is selected from a group consisting of (C6-10)aryl, (C3-10)cycloalkyl, (C3-10)heterocycloalkyl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl, wherein:
R3 may be substituted further by a radical selected from a group consisting of xe2x80x94X3NR8R21, xe2x80x94X3NR8C(O)R21, xe2x80x94X3NR8C(O)OR21, xe2x80x94X3NR8C(O)NR8R21, xe2x80x94X3NR8C(NR8)NR8R21, xe2x80x94X3OR21, xe2x80x94X3SR21, xe2x80x94X3S(O)R21, xe2x80x94X3S(O)2R21, xe2x80x94X3C(O)R21, xe2x80x94X3C(O)OR21, xe2x80x94X3OC(O)R21, xe2x80x94X3C(O)NR8R21, xe2x80x94X3OC(O)NR8R21, xe2x80x94X3S(O)2NR8R21, xe2x80x94X3P(O)(OR8)OR21, xe2x80x94X3OR52, xe2x80x94X3CONR8R52, xe2x80x94X3SO2NR8R52, xe2x80x94X3OP(O)(OR8)OR21 and xe2x80x94R21, wherein:
X3 is a bond or (C1-6)alkylene, R8 at each occurrence independently is hydrogen or (C1-6)alkyl, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2N(CH3)2 or xe2x80x94CH2CN, and R21 is xe2x80x94(C1-8)alkyl or xe2x80x94X3R22, wherein X3 is as defined above and R22 is selected from a group consisting of (C3-10)cycloalkyl, hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl, wherein:
R22 may be substituted further by a radical selected from a group consisting of xe2x80x94X3NR8R23, xe2x80x94X3NR8C(O)R23, xe2x80x94X3NR8C(O)OR23, xe2x80x94X3NR8C(O)NR8R23, xe2x80x94X3OR23, xe2x80x94X3NR8C(NR8)NR8R23, xe2x80x94X3SR23, xe2x80x94X3S(O)R23, xe2x80x94X3S(O)2R23, xe2x80x94X3C(O)R23, xe2x80x94X3OC(O)R23, xe2x80x94X3C(O)OR23, xe2x80x94X3C(O)NR8R23, xe2x80x94X3OC(O)NR8R23, xe2x80x94X3S(O)2NR8R23, xe2x80x94X3OR52, xe2x80x94X3CONR8R52, xe2x80x94X3SO2NR8R52, xe2x80x94X3P(O)(OR8)OR23, xe2x80x94X3OP(O)(OR8)OR23 and xe2x80x94R23, wherein:
X3 is a bond or (C1-6)alkylene and R8 at each occurrence independently is hydrogen or (C1-6)alkyl, R52 represents CH2CH2xe2x80x94N(CH2CH2OH)2, CH(CH3)CH2N(CH3)2, CH2CH2OH, CH2CH2N(CH3)2 or CH2CN, and R23 is (C1-8)alkyl or xe2x80x94X3R24, wherein X3 is as defined above and R24 is selected from a group consisting of (C3-10)cycloalkyl, hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl, wherein
R24 may be substituted further by a radical selected from a group consisting of xe2x80x94X3NR8R25, xe2x80x94X3NR8C(O)R25, xe2x80x94X3NR8C(O)OR25, xe2x80x94X3OR25, xe2x80x94X3NR8C(O)NR8R25, xe2x80x94X3NR8C(NR8)NR8R25, xe2x80x94X3SR25, xe2x80x94X3C(O)R25, xe2x80x94X3S(O)2R25, xe2x80x94X3C(O)R25, xe2x80x94X3OS(O)R25, xe2x80x94X3C(O)OR25, xe2x80x94X3C(O)NR8R25, xe2x80x94X3OC(O)NR8R25, xe2x80x94X3S(O)2NR8R25, xe2x80x94X3P(O)(OR8)OR25, xe2x80x94X3OR52, xe2x80x94X3CONR8R52, xe2x80x94X3SO2NR8R52, xe2x80x94X3OP(O)(OR8)OR25 and xe2x80x94R25, wherein:
X3 is a bond or (C1-6)alkylene and R8 at each occurrence independently is hydrogen or (C1-6)alkyl, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2N(CH3)2 or xe2x80x94CH2CN, and R25 is xe2x80x94(C1-8)alkyl or xe2x80x94X3R26, wherein X3 is as defined above and R26 is selected from a group consisting of (C3-10)cycloalkyl, hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl; wherein any of the (C3-10)cycloalkyl, hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C5-10)aryl, (C9-10)bicycloaryl and hetero(C8-10)bicycloaryl contained within R3, R22, R24 and R26 may be substituted further with up to five substituents selected from a group consisting of (C1-6)alkyl, (C1-6)alkylidene, cyano, halo, nitro, halo-substituted (C1-3)alkyl, xe2x80x94X3NR16R16, xe2x80x94X3NR16C(O)OR16, xe2x80x94X3NR16C(O)NR16R16, xe2x80x94X3NR16C(NR16)NR16R16, xe2x80x94X3OR16, xe2x80x94X3SR16, xe2x80x94X3C(O)OR16, xe2x80x94X3C(O)NR16R16, xe2x80x94X3S(O)2NR16R16, xe2x80x94X3P(O)(OR8)OR16, xe2x80x94X3OR52, xe2x80x94X3CONR8R52, xe2x80x94X3C(O)R16, xe2x80x94X3SO2NR8R52, xe2x80x94X3S(O)R17, xe2x80x94X3OP(O)(OR8)OR16, xe2x80x94X3NR16C(O)R17, xe2x80x94X3S(O)2R17 and xe2x80x94X3C(O)R16, wherein:
X3 is a bond or (C1-6)alkylene, R52 represents xe2x80x94CH2CH2xe2x80x94N(CH2CH2OH)2, xe2x80x94CH(CH3)CH2N(CH3)2, xe2x80x94CH2CH2OH, xe2x80x94CH2CH2N(CH3)2 or xe2x80x94CH2CN, R16 at each occurrence independently is selected from a group consisting of hydrogen, (C1-3)alkyl or halo-substituted (C1-3)alkyl and R17 is xe2x80x94(C1-3)alkyl or halo-substituted (C1-3)alkyl; and
the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers, and pharmaceutically acceptable salts thereof, with the proviso that only one of R3, R22, R24 and R26 represents a fused bicyclic ring structure; which process comprises:
(A) reacting a compound of Formula 2: 
xe2x80x83a with a compound of the formula NH2CR1R2CN, wherein X1, R1, R2 and R3 are as defined above; and
(B) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;
(C) optionally converting a salt form of a compound of Formula I to non-salt form;
(D) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;
(E) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;
(F) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers;
(G) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(H) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.
Pharmacology and Utility
The compounds of this invention are cysteine protease inhibitors. In particular the compounds of this invention inhibit the activity of cathepsins B, L, K and/or S and, as such, are useful for treating diseases in which cathepsin B, L, K and/or S activity contributes to the pathology and/or symptomatology of the disease. For example, the compounds of this invention are useful in treating tumor invasion and metastasis, in particular as anti-angiogenic agents, rheumatoid arthritis, osteo arthritis, pneumocystis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders. Furthermore, the compounds of this invention are useful in treating bone resorption disorders, e.g., osteoporosis. The compounds of this invention also are useful in treating autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves"" disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto""s thyroiditis. The compounds of this invention also are useful in treating allergic disorders, including, but not limited to asthma; and allogeneic immune responses, including, but not limited to, organ transplants or tissue grafts. In particular, the compounds of this invention are useful in treating osteoporosis in humans by inhibition of cathepsin K, particularly in treating post-menopausal women.
The cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Typically, the assay measures protease induced hydrolysis of a peptide based substrate. Details of assays for measuring protease inhibitory activity are set forth in Examples 11, 12, 13 and 14, infra.
Nomenclature
The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc. or by using the xe2x80x9cAutonomxe2x80x9d, a Beilstein Commander 2.1 Application, distributed by Beilstein. For example, a compound of Formula I in which:
X1 is CR6R7, R1 and R2 are hydrogen, R3 is biphenyl-3-yl, R6 is hydrogen and R7 is 2-methylpropyl is named 2-biphenyl-3-yl-N-cyanomethyl-4-methylpentanamide; or 2-biphenyl-3-yl-4-methyl-pentanoic acid cyanomethyl-amide.
Administration and Pharmaceutical Compositions
In general, compounds of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I may range from 0.1 micrograms per kilogram body weight (xcexcg/kg) per day to 10 milligram per kilogram body weight (mg/kg) per day, typically 1 xcexcg/kg/day to 1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 xcexcg/day to 100 mg/day, typically 0.1 mg/day to 10 mg/day. In general, one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.
The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, or the like). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.
The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01% w to 10% w, preferably 0.3% w to 1% w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical compositions is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula I are described in Example 15.
The compounds of Formula I can be administered alone or in combination with other compounds of Formula I or in combination with one or more other active ingredient(s). For example, the compounds of Formula I can be administered in combination with a therapeutically active amount of a bisphosphonic acid or acid ester derivative or any pharmaceutically acceptable salt thereof. Suitable bisphosphonic acids and acid ester derivatives include compounds corresponding to the following formula: 
wherein X7 is a bond or (C1-7)alkylene, each R27 independently is hydrogen or (C1-30)alkyl, R28 and R29 are selected independently from a group consisting of hydrogen, halo, optionally substituted (C1-30)alkyl, (C3-30)cycloalkyl, hetero(C5-30)cycloalkyl, optionally substituted (C6-10)aryl, hetero(C6-10)aryl, NR30R30, OR30, SR30, wherein each R30 independently is hydrogen, (C1-10)alkyl, (C3-10)cycloalkyl, optionally substituted (C6-10)aryl, provided that both R28 and R29 are not selected from hydrogen or hydroxy when X7 is a bond; or R28 and R29 taken together form (C2-9)alkylene; wherein (C3-10)cycloalkyl includes adamantyl and the like, hetero(C5-10)cycloalkyl includes pyrrolidinyl and the like, (C6-10)aryl includes phenyl and naphthyl, and hetero(C6-10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like.
Instances wherein R28 and/or R29 are substituted (C1-30)alkyl may include, but are not limited to, (C1-30)alkyl substituted by hetero(C5-10)cycloalkyl, (C6-10)aryl, hetero(C6-10)aryl, NR31R31, OR31 and SR31, wherein each R31 is independently hydrogen or (C1-10)alkyl; wherein hetero(C5-10)cycloalkyl includes pyrrolidinyl and the like, (C6-10)aryl includes phenyl and naphthyl, and hetero(C6-10)aryl includes quinolyl, isoquinolyl, pyridyl, furyl, imidazolyl, imidazopyridyl and the like. Suitable optionally substituted aryl groups include, but are not limited to, halo-substituted phenyl.
A non-limiting class of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R28 is selected from the group consisting of hydrogen, hydroxy or halo, and R29 is selected from the group consisting of optionally substituted (C1-30)alkyl, halo and SR30, wherein R30 is (C1-10)alkyl or phenyl.
A non-limiting subclass of bisphosphonic acids and acid ester derivatives thereof suitable for administration in combination with compounds of Formula I include those in which R28 is selected from the group consisting of hydrogen, hydroxy and chloro and R29 is selected from the group consisting of optionally substituted (C1-30)alkyl, chloro and chlorophenylthio.
A non-limiting example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I include that in which X7 is a bond, each R27 is hydrogen, R28 is hydroxy and R29 is 3-aminopropyl, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (aka alendronic acid), or the monosodium trihydrate salt thereof, namely 4-amino-1-hydroxybutylidene-1,1-bisphosphonate monosodium trihydrate (aka alendronate monosodium trihydrate), described in U.S. Pat. No. 4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to Kieczykowski et al., issued May 28, 1991; U.S. Pat. No. 5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S. Pat. No. 5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which patents are incorporated by reference herein in their entirety.
Further non-limiting examples of bisphosphonic acids suitable for administration in combination with compounds of Formula I include the following:
cycloheptylaminomethylene-1,1-bisphosphonic acid (aka cimadronic acid), described in U.S. Pat. No. 4,970,335, to Isomura et al., issued Nov. 13, 1990;
1,1-dichloromethylene-1,1-diphosphonic acid (aka clodronic acid) and the disodium salt thereof, namely clodronate disodium, described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967);
1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid (aka EB-1053);
1-hydroxyethylidene-1,1-diphosphonic acid (aka etidronic acid);
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid (aka ibandronic acid), described in U.S. Pat. No. 4,927,814, issued May 22, 1990;
6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (aka neridronic acid);
3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (aka olpadronic acid);
3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (aka pamidronic acid);
2-pyrid-2-ylethylidene-1,1-bisphosphonic acid (aka piridronic acid), described in U.S. Pat. No. 4,761,406;
1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid (aka risedronic acid);
4-chlorophenylthiomethylenebisphosphonic acid (aka tiludronic acid), described in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24, 1989; and
1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (aka zoledronic acid); all of which patents and other documents referred to above are incorporated by reference herein in their entirety.
A non-limiting subclass of bisphosphonic acids suitable for administration in combination with compounds of Formula I include those selected from the group consisting of alendronic acid, cimadronic acid, clodronic acid, tiludronic acid, etidronic acid, ibandronic acid, risedronic acid, piridronic acid, pamidronic acid, zolendronic acid, pharmaceutically acceptable salts thereof, and mixtures thereof. A further example of a bisphosphonic acid suitable for administration in combination with compounds of Formula I is alendronic acid or a pharmaceutically acceptable salt thereof, and mixtures thereof. A further non-limiting example is alendronate monosodium trihydrate.
Compounds of Formula I can be administered in combination with a therapeutically active amount of an estrogen receptor agonist. Non-limiting examples of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include naturally occurring estrogens such as estradiol, estrone and estroil, or synthetic estrogen receptor agonists such as [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-(2-piperidin-1-ylethoxy)phenyl]methanone (aka raloxifene) and {2-[4-(1,2-diphenylbut-1-enyl)phenoxy]ethyl}dimethylamine (aka tamoxifen). A non-limiting subclass of estrogen receptor agonists suitable for administration in combination with the compounds of Formula I include estrogen receptor partial agonists (i.e., estrogen receptor agonists with mixed agonist/antagonist properties), sometimes referred to as estrogen receptor modulators. Estrogen receptor partial agonists can exert tissue-selective estrogen agonist effects. Tamoxifen, for example, selectively exerts an estrogen agonist effect on the bone, in humans. Additional suitable estrogen receptor partial agonists are described in Tissue-Selective Actions Of Estrogen Analogs, Bone Vol. 17, No. 4, October 1995, 181S-190S. Certain 3-[4-(2-phenylindol-1-ylmethyl)phenyl]acrylamides, described in U.S. Pat. No. 5,985,910 to Miller et al., Nov. 16, 1999; benzothiphene compounds, described in U.S. Pat. No. 5,985,897 to Meuhl et al., Nov. 16, 1999; naphthyl compounds, described in U.S. Pat. No. 5,952,350 to Cullinan et al., Sep. 14, 1999; substituted benzothiophene compounds, described in U.S. Pat. No. 5,962,475 to Schmid et al., Oct. 4, 1999, are suitable estrogen receptor partial agonists for administration with the compounds of Formula I; all of which patents and other documents referred to above are incorporated by reference herein in their entirety.
More particularly a pharmaceutical composition of this invention may comprise a therapeutically effect amount of a compound of Formula I in combination with one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effect amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effect amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipient(s). Non-limiting examples of such bisphosphonic acids include 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof; particularly 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof and preferably 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.
Chemistry
Compounds of Formula I can be prepared by proceeding as in the following Reaction Scheme 1: 
in which X1, R1, R2 and R3 are as defined in the Summary of the Invention.
Compounds of Formula I can be prepared by condensing an acid of Formula 2 with an aminoalkanonitrile of the formula NH2CR1R2CN. The condensation reaction can be effected with an appropriate coupling agent (e.g., benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP(copyright)), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), or the like) and non-nucleophillic base (e.g., N-methylmorpholine, triethylamine, or the like, or any suitable combination thereof) in a suitable solvent (N-methylpyrrolidinone, or the like) at ambient temperature and requires 3 to 10 hours to complete the reaction. A detailed description for the synthesis of a compound of Formula I by the processes in Reaction Scheme 1 is set forth in Examples 7, 8 and 9, infra.
Compounds of Formula I in which R3 is substituted phenyl can be prepared by proceeding as in the following Reaction Scheme 2: 
in which X1, R2 and R21 are as defined in the Summary of the Invention.
Compounds of Formula I in which R3 is substituted phenyl can be prepared by reacting a boronic ester of Formula 8 with a compound of the formula R21Br. The reaction is carried out in a suitable solvent (e.g., N,N-dimethylformamide (DMF), 2-propanol, or the like) in the presence of sodium bicarbonate and palladium(II) chloride under nitrogen at 80 to 85xc2x0 C. and requires 1 to 5 hours to complete the reaction. A detailed description for the synthesis of a compound of Formula I by the processes in Reaction Scheme 2 is set forth in Example 10, infra.
Compounds of Formula 2 in which X1 is CHR7 can be prepared by reacting a compound of Formula 3: 
with a compound of the formula R7L in which L is a leaving group, R25 is hydrogen or (C1-6)alkyl and R3 and R7 are as defined in the Summary of the Invention for Formula I. The reaction is carried out in a suitable solvent (e.g., dimethoxyethane, dioxane, ether, hexane, tetrahydrofuran (THF), or the like) and in the presence of a strong non-nucleophillic base (e.g., lithium diisopropylamide (LDA), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS), potassium tert-butoxide, sodium methoxide, tert-butyl lithium, or the like) at approximately xe2x88x9278xc2x0 C. and requires 1 to 2 hours to complete the reaction.
Compounds of Formula 2 in which R3 is optionally substituted 4-phenylthiazol-2-yl can be prepared by reacting a compound of Formula 4: 
with a compound of Formula RC(O)CH2L in which L is a leaving group and R is optionally substituted phenyl to provide a corresponding 2-(4-phenylthiazol-2-yl)acetate or 4-phenylthiazol-2-ylcarbamate and then hydrolyzing to the corresponding compound of Formula 2. The reaction with the compound of Formula 4 is carried out in a suitable solvent (e.g., ethanol, acetonitrile, THF, methanol, DMF, or the like) at reflux and requires 0.5 to 1 hour to complete the reaction. Hydrolysis can be effected by treating the ester with base (e.g., sodium hydroxide, lithium hydroxide, or the like) in a suitable solvent (methanol, THF/water, DMF/water, acetonitrile/water, or the like) for 2 to 6 hours.
Chiral compounds of Formula 2 in which X1 is CHR7 can be prepared by condensing a compound of Formula 5: 
with a compound of the formula R3L, wherein L is a leaving group, R26 is a chiral auxiliary, e.g., isopropyl or benzyl, and X1, R3 and R7 are as defined in the Summary of the Invention, to provide a compound of Formula 6: 
and then converting the compound of Formula I to the corresponding acid. The condensation reaction is carried out is a suitable solvent (e.g., THF, dimethoxymethane, ether, or the like) and in the presence of a strong non-nucleophilic, hydrocarbon-soluble base (e.g., NaHMDS, KHMDS, or the like) at about xe2x88x9278xc2x0 C. to about xe2x88x9210xc2x0 C. and requires approximately 1 hour for the reaction to complete the reaction. Conversion to the corresponding acid can be effected by treating the compound of Formula 6 with lithium hydroxide monohydrate and hydrogen peroxide in a suitable solvent (e.g., THF/water, or the like) at ambient temperature for 1 to 16 hours.
Compounds of Formula 4 can be prepared by reacting a corresponding 2-cyanoacetate or cyanocarbamate with hydrogen sulfide gas. The reaction is carried out in a suitable solvent (e.g., pyridine, triethylamine, dioxane, or the like) and in the presence of a suitable non-nucleophillic base (e.g., triethylamine, pyridine, diisopropylethylamine, or the like) at approximately 0xc2x0 C. and requires 3 to 5 hours to complete the reaction. A detailed description for the synthesis of a compound of Formula 2 in which R3 is optionally substituted 4-phenylthiazol-2-yl is set forth in Example 4, infra.
Compounds of Formula 2 in which R3 is 2-substituted thiazol-4-yl can be prepared by reacting a compound of Formula 7: 
with a compound of the formula RC(S)NH2, in which L is a leaving group, R is an appropriate substituent and X1 is as described in the Summary of the Invention, to provide a corresponding acetate or carbamate and then hydrolyzing to the corresponding compound of Formula 2. The reaction with the compound of Formula 7 is carried out in a suitable solvent (e.g., ethanol, methanol, DMF, dioxane, or the like) at reflux and requires 1 to 2 hours to complete the reaction. Hydrolysis can be effected by treating the ester with base (e.g., sodium hydroxide, lithium hydroxide, or the like) in a suitable solvent (methanol, THF/water, DMF/water, acetonitrile/water, or the like) for 2 to 6 hours.
Compounds of Formula 7 in which L is bromo can be prepared by treating a corresponding acetylacetate or acetylcarbamate with bromine in a suitable solvent (e.g., methylene chloride, chloroform, carbon tetrachloride, chlorobenzene, or the like) at approximately 0xc2x0 C. for 12 to 15 hours. Detailed descriptions for the synthesis of compounds of Formula 2 are set forth in Examples 1, 2, 3, 4, 5 and 6, infra.
Additional Processes for Preparing Compounds of Formula I
A compound of Formula I can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of Formula I can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, or the like). A compound of Formula I in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, or the like).
The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chloride) at approximately 0xc2x0 C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent (e.g. sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80xc2x0 C.
Prodrug derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art (e.g., for further details see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters. 4: 1985). For example, appropriate drugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like).
Protected derivatives of the compounds of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. 1981.
Compounds of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, and the like) and can be readily separated by taking advantage of these dissimilarities. The diastereomers can be separated by chromatography or, preferable, by separation/resolution techniques based upon differences in solubility. The optically pure enatiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons, Inc. (1981).
In summary, the compounds of Formula I are made by a process which comprises:
(A) reacting a compound of Formula 2: 
xe2x80x83with a compound of the formula NH2CR1R2CN, wherein X1, R1, R2 and R3 are as defined in the Summary of the Invention; and
(B) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;
(C) optionally converting a salt form of a compound of Formula I to non-salt form;
(D) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;
(E) optionally converting an N-oxide form of a compound of Formula I its unoxidized form;
(F) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers;
(G) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and
(H) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.